title: Melanocortins protect against progression of Alzheimer's disease in triple-transgenic mice by targeting multiple pathophysiological pathways.
abstract: Besides specific triggering causes, Alzheimer's disease (AD) involves pathophysiological pathways that are common to acute and chronic neurodegenerative disorders. Melanocortins induce neuroprotection in experimental acute neurodegenerative conditions, and low melanocortin levels have been found in occasional studies performed in AD-type dementia patients. Here we investigated the possible neuroprotective role of melanocortins in a chronic neurodegenerative disorder, AD, by using 12-week-old (at the start of the study) triple-transgenic (3xTg-AD) mice harboring human transgenes APPSwe, PS1M146V, and tauP301L. Treatment of 3xTg-AD mice, once daily until the end of the study (30 weeks of age), with the melanocortin analog [Nle(4),D-Phe(7)]-α-melanocyte-stimulating hormone (NDP-α-MSH) reduced cerebral cortex/hippocampus phosphorylation/level of all AD-related biomarkers investigated (mediators of amyloid/tau cascade, oxidative/nitrosative stress, inflammation, apoptosis), decreased neuronal loss, induced over-expression of the synaptic activity-dependent gene Zif268, and improved cognitive functions, relative to saline-treated 3xTg-AD mice. Pharmacological blockade of melanocortin MC4 receptors prevented all neuroprotective effects of NDP-α-MSH. Our study identifies, for the first time, a class of drugs, MC4 receptor-stimulating melanocortins, that are able to counteract the progression of experimental AD by targeting pathophysiological mechanisms up- and down-stream of β-amyloid and tau. These data could have important clinical implications.
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, Section of Pharmacology and Molecular Medicine, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Giuliani
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bitto
authors.forename: Maria
authors.initials: M
authors.lastname: Galantucci
authors.forename: Davide
authors.initials: D
authors.lastname: Zaffe
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ottani
authors.forename: Natasha
authors.initials: N
authors.lastname: Irrera
authors.forename: Laura
authors.initials: L
authors.lastname: Neri
authors.forename: Gian Maria
authors.initials: GM
authors.lastname: Cavallini
authors.forename: Domenica
authors.initials: D
authors.lastname: Altavilla
authors.forename: Annibale R
authors.initials: AR
authors.lastname: Botticelli
authors.forename: Francesco
authors.initials: F
authors.lastname: Squadrito
authors.forename: Salvatore
authors.initials: S
authors.lastname: Guarini
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D008297:Male; D053486:Melanocortins / Q000494:pharmacology* / Q000627:therapeutic use*; D051379:Mice; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000235:genetics; D044105:Receptor, Melanocortin, Type 4 / Q000502:physiology; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D053486:Melanocortins; D018696:Neuroprotective Agents; D044105:Receptor, Melanocortin, Type 4; D016875:tau Proteins
keywords: Alzheimer's disease; Learning and memory; Melanocortins; Neuroprotection; Pathophysiological pathways; Triple-transgenic mice